Plaster having laminated support

ABSTRACT

A patch comprising a laminated backing layer and a drug-containing pressure-sensitive adhesive layer, wherein the laminated backing layer consists of a knitted fabric laminated on one side of a polyester film, and the drug-containing pressure-sensitive adhesive layer is laminated on the other side of the polyester film, wherein the knitted fabric has a 30% longitudinal modulus of 0.1 kg/5 cm to 20 kg/5 cm and a 30% lateral modulus of not more than 10 kg/5 cm, and a 30% longitudinal modulus/30% lateral modulus ratio of not less than 2.

TECHNICAL FIELD

The present invention relates to a patch laminated with adrug-containing pressure-sensitive adhesive layer onto a laminatedbacking layer.

BACKGROUND ART

In the case of most pharmaceuticals, the drugs are orally administeredin the form of tablets, capsules, syrups or the like. However, orallyadministered drugs are associated with certain drawbacks, such as highsusceptibility to the first pass effect in the liver after theirabsorption or temporary blood levels in excess of requirement afteradministration, and the consequent side effects. Development ofmedicinal patches has been actively pursued with the goal of avoidingthe drawbacks of oral administration. Patches not only compensate forthese drawbacks but also offer benefits such as reduced administrationfrequency, better compliance and ease of both administration and itstermination, and are particularly useful for elderly and infantpatients.

The development of patches has led to increasingly stricter requirementsfor backing layers in recent years. In particular, patch backing layersis required to be flexible and exhibit no curling, and to have barrierproperty against drugs, i.e., drugs are not adsorbed onto the backinglayers.

Research has therefore been carried out on various types of backinglayers having such properties, and for example, Japanese PatentApplication Laid-Open No. HEI 5-309128 discloses a patch comprising apressure-sensitive adhesive layer laminated on the nonwoven fabric sideof a backing layer obtained by laminating a polyester film with athickness of 0.5-6 μm and a polyester nonwoven fabric with a basisweight of 5-20 g/m². Also, Japanese Patent Application Laid-Open No. HEI8-104622 discloses a backing layer obtained by laminating a polymer filmwith a 50% modulus of 0.1-2.5 kg/5 cm, such as polyethylene orethylene-vinyl acetate copolymer, with a nonwoven fabric or woven fabrichaving a 50% modulus of 0.1-1.5 kg/5 cm and a drape coefficient of0.3-0.7. In addition, Japanese Patent No. 2505674 discloses a patchemploying a solid fine particle-containing polyester film with athickness of 0.5-4.9 μm and having a specific strength and ductility,wherein a backing layer sheet is laminated on the film.

However, patches employing such conventional backing layers have beeninadequate from the viewpoint of flexibility, easily undergo curling,and are still lacking in terms of attachment ease, adhesion to skin andcomfortability, while an additional disadvantage has been adsorption ofdrugs into the backing layers which impedes satisfactory permeation intothe skin. No patch has yet been developed which satisfies all of theserequired properties.

DISCLOSURE OF THE INVENTION

The present invention has been accomplished in light of theaforementioned problems associated with the prior art, and its object isto provide a patch which has excellent flexibility, does not exhibitcurling, is easy to attach and has excellent adhesion andcomfortability, while also avoiding adsorption of the drug into thebacking layer and thus ensuring adequate skin permeation of the drug.

As a result of much diligent research directed toward achieving theobject stated above, the present inventors have discovered that bylaminating a drug-containing pressure-sensitive adhesive layer on alaminated backing layer comprising a knitted fabric with specificproperties laminated with a polyester film, it is possible to obtain apatch which is adequately resistant to curling and maintains a highlevel of flexibility, attachment ease, adhesion and comfortability whilealso satisfactorily preventing adsorption of the drug onto the backinglayer. The present invention has been completed on the basis of thisdiscovery.

Specifically, the patch of the invention is a patch comprising alaminated backing layer and a drug-containing pressure-sensitiveadhesive layer, wherein the laminated backing layer consisting of aknitted fabric laminated on one side of a polyester film, and thedrug-containing pressure-sensitive adhesive layer is laminated on theother side of the polyester film, wherein the knitted fabric has a 30%longitudinal modulus of 0.1 kg/5 cm to 20 kg/5 cm and a 30% lateralmodulus of not more than 10 kg/5 cm, and a 30% longitudinal modulus/30%lateral modulus ratio of not less than 2.

Since the backing layer in the patch of the invention consists of aknitted fabric and a polyester film, and the 30% moduli of the knittedfabric in the different perpendicular directions (longitudinal andlateral directions) are in specific ranges and ratio, the flexibility isexcellent and curling is adequately prevented even after lamination ofthe polyester film, while the patch having the laminated backing layeris also easy to attach to the body and the skin adhesion andcomfortability are particularly excellent. In addition, since adrug-containing pressure-sensitive adhesive layer is laminated on thepolyester film side of the laminated backing layer, drug adsorption ontothe laminated backing layer is adequately prevented and skin permeationof the drug is therefore sufficient to produce a therapeutic effect.

BEST MODE FOR CARRYING OUT THE INVENTION

The patch of the invention comprises a laminated backing layer and adrug-containing pressure-sensitive adhesive layer, wherein the laminatedbacking layer consisting of a knitted fabric laminated on one side of apolyester film, and the drug-containing pressure-sensitive adhesivelayer is laminated on the other side of the polyester film.

The laminated backing layer according to the invention will be explainedfirst. The knitted fabric in the laminated backing layer of theinvention has a cloth texture or structure wherein loops (stitches) areformed with yarn and the loops are alternately laced forward/backwardand left/right, and thus it differs from woven fabrics or nonwovenfabrics. Because this type of knitted fabric has flexibility, elasticityand a soft feel, it is suitable as a patch backing layer. On the otherhand, direct lamination of a drug-containing pressure-sensitive adhesivelayer on a knitted fabric results in adsorption of the drug into thebacking layer, and therefore according to the present invention, apolyester film with a high barrier property (drug barrier property) issituated between the knitted fabric and the pressure-sensitive adhesivelayer to prevent adsorption of the drug into the backing layer and toachieve sufficient permeation of the drug into the skin for atherapeutic effect.

According to the invention, the knitted fabric used has a 30%longitudinal modulus of 0.1 kg/5 cm to 20 kg/5 cm and a 30% lateralmodulus of not more than 10 kg/5 cm, and a 30% longitudinal modulus/30%lateral modulus ratio of not less than 2. By using this manner ofknitted fabric it is possible to obtain a laminated backing layer havingexcellent flexibility and adequate resistance to curling even thoughlaminated with the polyester film, while the patch provided with thelaminated backing layer is easily attached to the human body andexhibits a high level of skin adhesion and comfortability.

Here, the longitudinal direction is the machine direction during theprocess of fabricating the knitted fabric, while the lateral directionis the direction perpendicular to the longitudinal direction, or inother words, the direction of width. The 30% longitudinal modulus of theknitted fabric of the invention is 0.1 kg/5 cm to 20 kg/5 cm, preferably0.2 kg/5 cm to 15 kg/5 cm and more preferably 0.4 kg/5 cm to 12 kg/5 cm.If the 30% longitudinal modulus is less than 0.1 kg/5 cm, the knittedfabric is too soft and curling (or “warping”) occurs in the longitudinaldirection (machine direction) after lamination with the polyester film.On the other hand, a 30% longitudinal modulus of more than 20 kg/5 cmimpairs the flexibility of the laminated backing layer and reduces thecomfortability and skin adhesion of the obtained patch.

The 30% lateral modulus of the knitted fabric of the invention is notmore than 10 kg/5 cm, preferably 0.1-8 kg/5 cm and more preferably 0.3-5kg/5 cm. Since curling of the backing layer comprising the knittedfabric laminated with the polyester film tends to occur in thelongitudinal direction, i.e. the machine direction during the process oflamination, a 30% lateral modulus of more than 10 kg/5 cm impairs theflexibility of the laminated backing layer and reduces thecomfortability and skin adhesion of the obtained patch. On the otherhand, a 30% lateral modulus below the aforementioned minimum results ina knitted fabric which is too soft and is more susceptible to curlingafter lamination with the polyester film.

According to the invention, even when using a knitted fabric with a 30%longitudinal modulus and 30% lateral modulus in the ranges specifiedabove, if the 30% longitudinal modulus/30% lateral modulus ratio is lessthan 2, the softness in the laminating lateral direction during theprocess of laminating the knitted fabric and the polyester film (thedirection of width during the process of lamination) becomes moreinfluential, and curling also occurs in the lateral direction (widthdirection). The knitted fabric of the invention must have a 30%longitudinal modulus of 0.1 kg/5 cm to 20 kg/5 cm and a 30% lateralmodulus of not more than 10 kg/5 cm, as well as a 30% longitudinalmodulus/30% lateral modulus ratio of not less than 2 and preferably a30% longitudinal modulus/30% lateral modulus ratio of not less than 3.There is no particular restriction on the upper limit of the 30%longitudinal modulus/30% lateral modulus ratio, but if the ratio is toolarge there will be a tendency toward slight deformation after cuttingof the patch to the prescribed size, and therefore it is preferably notmore than 20.

Throughout the present specification, “30% modulus” (30% longitudinalmodulus or 30% lateral modulus) is the value measured according to themethod of JIS L1018 (Cut strip method).

There are no particular restrictions on the material of the fiberscomposing the knitted fabric having the specific properties describedabove, but a polyester knitted fabric is preferred for betterflexibility and elasticity, and from the standpoint of safety andgeneral purpose use, a polyethylene terephthalate knitted fabric isespecially preferred.

The basis weight of the knitted fabric is not particularly restricted,but if the basis weight is too low the handling properties will tend tobe less than satisfactory, and if the basis weight is too high theflexibility and elasticity may be inadequate resulting in hardness; arange of 10-200 g/m² is therefore preferred.

There are also no restrictions on the thickness of the laminated backinglayer consisting of the knitted fabric laminated on the polyester film,but if it is too thin the handling properties may be so poor as todiminish the ease of attachment, and if it is too thick the flexibilityand elasticity may be so inadequate as to result in hardness, while alsotending to promote fold-over during attachment; a range of 0.05-1 mm istherefore preferred.

According to the invention, the material of the polyester film laminatedon the knitted fabric is not particularly restricted so long as it is apolyester, but a polyethylene terephthalate film is preferred from thestandpoint of flexibility, safety and general purpose use. There arealso no particular restrictions on the thickness of the polyester film,but if it is too thin it will be more susceptible to wrinkling when itis laminated during the process of lamination with the knitted fabric,and if it is too thick the flexibility will tend to be insufficient; arange of 0.5-12 μm is therefore preferred.

The polyester film of the invention has a longitudinal ductility ofpreferably at least 0.5% and less than 30%, and more preferably between2% and 25%. With a longitudinal ductility of less than 0.5%, theflexibility of the laminated backing layer may be impaired and thecomfortability and skin adhesion of the obtained patch will tend to bereduced. On the other hand, with a longitudinal ductility of not lessthan 30%, curling tends to occur more easily in the longitudinaldirection.

The polyester film of the invention has a lateral ductility ofpreferably at not less than 2%, and more preferably not less than 4% andnot more than 50%. With a lateral ductility of less than 2%, theflexibility of the laminated backing layer may be impaired and thecomfortability and skin adhesion of the obtained patch will tend to bereduced. On the other hand, with a lateral ductility exceeding theaforementioned maximum, curling tends to occur more easily in thelateral direction.

Throughout the present specification, “ductility” (longitudinalductility or lateral ductility) is the value measured in the mannerdescribed below, according to the tensile strength measuring methoddescribed in “Bandages” in the Japanese Pharmacopoeia. Specifically, a12 mm-wide, 200 mm-long test piece is prepared, placed in a desiccatorpreviously saturated with vapor of a saturated sodium nitrite solution,and allowed to stand for 4 hours at ordinary temperature. The gaugelength is adjusted to 150 mm (length before pulling=150 mm) with apendulum tester, and both ends of the test piece are gripped with 25-50mm wide anchors and pulled at a speed of 300 mm/min, after which thelength at the time of cutting is measured. The ductility is calculatedby the following formula based on the obtained measured value.Ductility [%]={((length at the time of cutting)−(length beforepulling))/(length before pulling)}×100

The laminated backing layer of the invention which consists of theaforementioned knitted fabric laminated on the polyester film hasexcellent flexibility, and its stiffness as an indicator of theflexibility is preferably not more than 30 mg and more preferably from 3mg to 20 mg. If the stiffness is more than 30 mg, the flexibility of thelaminated backing layer may be impaired and the comfortability and skinadhesion of the obtained patch will tend to be reduced. On the otherhand, with a stiffness of less than the aforementioned minimum, thelaminated backing layer tends to be too soft and the attachment easetends to be reduced. Throughout the present specification, the“stiffness” is the value measured according to the method described inJIS L1096 (Gurley method).

The laminated backing layer of the invention preferably has the knittedfabric and polyester film adhesively laminated by an adhesive. There areno particular restrictions on the adhesive used, but it is preferably anadhesive comprising a hydrocarbon-based polymer and a tackifier, inorder to result in satisfactory adhesion between the knitted fabric andpolyester film. As hydrocarbon-based polymers there may be mentionedstyrene-isoprene-styrene block copolymer, styrene-butadiene-styreneblock copolymer, styrene-butadiene rubber, isoprene rubber,polyisobutylene and the like, but highly safe styrene-isoprene-styreneblock copolymer is most preferred. As tackifiers there may be mentionedrosin derivatives (rosins, rosin glycerin esters, hydrogenated rosins,hydrogenated rosin glycerin esters, rosin pentaerythritol esters, etc.),alicyclic saturated hydrocarbon resins (ALCON P100 (Arakawa ChemicalCo., Ltd.), etc.), aliphatic hydrocarbon resins (QUINTON B-170 (NihonZeon), etc.) terpene resins (YS resin PX-1150 (Yasuhara Chemical), etc.)and the like, and the tackifier content in the adhesive will generallybe about 30-90 wt %.

For the patch of the invention, against the laminated backing layerconsisting of a knitted fabric laminated on one side of theaforementioned polyester film, a drug-containing pressure-sensitiveadhesive layer is further laminated on the other side of the polyesterfilm. The composition of the drug-containing pressure-sensitive adhesivelayer is not particularly restricted, and will normally contain suitablepolymer materials, organic acids, absorption enhancers, plasticizers,tackifiers and the like in addition to the drug.

The types of drugs to be used for the invention are not particularlyrestricted so long as they are transdermally absorbed drugs, and asexamples there may be mentioned hypnotics/sedatives (flurazepamhydrochloride, rilmazafone hydrochloride, phenobarbital, amobarbital,etc.), antipyretic antiphlogistic analgesics (butorphanol tartrate,perisoxal citrate, acetaminophen, mefenamic acid, diclofenac sodium,aspirin, alclofenac, ketoprofen, flurbiprofen, naproxen, piroxicam,pentazocine, indomethacin, glycol salicylate, aminopyrine, loxoprofen,etc.), steroidal anti-inflammatory agents (hydrocortisone, prednisolone,dexamethasone, betamethasone), analeptic psychostimulants(methamphetamine hydrochloride, methylphenidate hydrochloride, etc.),psychoneural agents (imipran hydrochloride, diazepam, sertralinehydrochloride, fluvoxamine maleate, paroxetine hydrochloride, citalopramhydrobromide, fluoxetine hydrochloride, alprazolam, haloperidol,clomipramine, amitriptyline, desipramine, amoxapine, maprotiline,mianserin, setiptiline, trazadone, lofepramine, milnacipran, duloxetine,venlafexine, chlorpromazine hydrochloride, thioridazine, diazepam,meprobamate, etizolam, etc.), hormone agents (estradiol, estriol,progesterone, norethisterone acetate, methenolone acetate, testosterone,etc.), local anesthetics (lidocaine hydrochloride, procainehydrochloride, tetracaine hydrochloride, dibucaine hydrochloride,propitocaine hydrochloride, etc.), urinary tract agents (oxybutyninhydrochloride, tamsulosin hydrochloride, propiverine hydrochloride, etc.), skeletal muscle relaxants (tizanidine hydrochloride, eperisonehydrochloride, pridinol mesylate, suxamethonium hydrochloride, etc.),genital tract agents (ritodrine hydrochloride, meluadrine tartrate,etc.), antiepileptics (sodium valproate, clonazepam, carbamazepine,etc.), autonomic agents (carpronium chloride, neostigmine bromide,bethanechol chloride, etc.), antiparkinsonian agents (pergolidemesylate, bromocriptine mesylate, trihexyphenidyl hydrochloride,amantadine hydrochloride, ropinirole hydrochloride, talipexolehydrochloride, cabergoline, droxidopa, biperiden, selegilinehydrochloride, etc.), diuretics (hydroflumethiazide, furosemide, etc.),respiratory stimulants (loberine hydrochloride, dimorpholamine, naloxonehydrochloride, etc.), anti-migraine agents (dihydroergotamine mesylate,sumatriptan, ergotamine tartrate, flunarizine hydrochloride,cyproheptadine hydrochloride, etc.), antihistamines (clemastinefumarate, diphenhydramine tannate, chlorpheniramine maleate,diphenylpyraline hydrochloride, promethazine, etc.), bronchodilators(tulobuterol hydrochloride, procaterol hydrochloride, salbutamolsulfate, clenbuterol hydrochloride, fenoterol hydrobromide, terbutalinesulfate, isoprenaline sulfate, formoterol fumarate, etc.), cardiacstimulants (isoprenaline hydrochloride, dopamine hydrochloride),coronary vasodilators (diltiazem hydrochloride, verapamil hydrochloride,isosorbide dinitrate, nitroglycerin, nicorandil, etc.), peripheralvasodilators (nicametate citrate, tolazoline hydrochloride, etc.), stopsmoking aids (nicotine, etc.), cardiovascular drugs (flunarizinehydrochloride, nicardipine hydrochloride, nitrendipine, nisoldipine,felodipine, amlodipine besylate, nifedipine, nilvadipine, manidipinehydrochloride, benidipine hydrochloride, enalapril maleate, temocaprilhydrochloride, alacepril, imidapril hydrochloride, cilazapril,lisinopril, captopril, trandolapril, perindopril elbumin, atenolol,pindolol, bisoprolol fumarate, metoprolol tartrate, betaxololhydrochloride, timolol maleate, bopindolol malonate, nipradilol,arotinolol hydrochloride, celiprolol hydrochloride, carvedilol,amosulalol hydrochloride, carteolol hydrochloride, bevantrolhydrochloride, terazosin hydrochloride, bunazosin hydrochloride,prazosin hydrochloride, doxazocine mesylate, valsartan, candesartancilexetil, losartan potassium, clonidine hydrochloride, guanfacinehydrochloride, guanabenz acetate, etc.), antiarrhythmics (propranololhydrochloride, alprenolol hydrochloride, procainamide hydrochloride,mexitilene hydrochloride, nadolol, disopyramide, etc.), anti-malignantulcer agents (cyclophosphamide, fluorouracil, tegafur, procarbazinehydrochloride, ranimustine, irinotecan hydrochloride, fluridine, etc.),hypolipidemic drugs (pravastatin, simvastatin, bezafibrate, probucol,etc.), hypoglycemic agents (glibenclamide, chlorpropamide, tolbutamide,glymidine sodium, glybuzole, buformine hydrochloride, etc.), pepticulcer agents (proglumide, cetraxate hydrochloride, spizofurone,cimetidine, glycopyrronium bromide, etc.), choleretic agents(ursodesoxycholic acid, osalmid, etc.), enterokinesis ameliorators(domperidone, cisapride, etc.), hepatic disease drugs (tiopronin, etc.),antiallergic agents (ketotifen fumarate, azelastine hydrochloride,etc.), antiviral agents (aciclovir, etc.), antivertigo agents(betahistine mesylate, difenidol hydrochloride, etc.), antibiotics(cefaloridine, cefdinir, cefpodoxime proxetil, cefaclor, clarithromycin,erythromycin, methylerythromycin, kanamycin sulfate, cycloserine,tetracycline, benzylpenicillin potassium, propicillin potassium,cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride,carbenicillin sodium, chloramphenicol, etc.), agents for addictivedependence (cyanamide, etc.), anorectic agents (mazindol, etc.),chemotherapeutics (isoniacide, ethionamide, pyrazinamide, etc.), bloodclotting promoters (ticlopidine hydrochloride, warfarin potassium,etc.), anti-Alzheimer drugs (physostigmine, donepezil hydrochloride,tacrine, arecoline, xanomeline, etc.), serotonin receptor-antagonisticantiemetics (ondansetron hydrochloride, granisetron hydrochloride,ramosetron hydrochloride, azasetron hydrochloride, etc.), gouttherapeutic agents (colchicine, probenecid, sulfinpyrazone, etc.), andnarcotic analgesics (fentanyl citrate, morphine sulfate, morphinehydrochloride, codeine phosphate, cocaine hydrochloride, pethidinehydrochloride, etc.).

These drugs may be used alone or in combinations of two or more, and thedrugs may be included in the form of inorganic salts, organic salts orfree bases. Such drugs may be appropriately compounded, usually in therange of 0.1-60 wt % based on the weight of the total composition of thepressure-sensitive adhesive layer, taking into account adequatepermeation of the patch, and reducing redness or other irritation of theskin.

Polymer materials which may be added to the pressure-sensitive adhesivelayer in the patch of the invention are not particularly restricted, andthere may be mentioned rubber-based polymers such asstyrene-isoprene-styrene block copolymer, styrene-butadiene-styreneblock copolymer, styrene-butadiene rubber and isoprene rubber,acrylic-based polymers, silicone-based polymers and the like, which maybe used alone or in combinations of two or more.

Such polymer materials are appropriately added in a range of preferably5-80 wt %, more preferably 10-70 wt % and most preferably 10-60 wt %,based on the weight of the total composition of the pressure-sensitiveadhesive layer, taking into account formation of the pressure-sensitiveadhesive layer and achieving adequate skin permeation of the drug.

An organic acid may also be added to the pressure-sensitive adhesive inthe patch of the invention. As such organic acids there may be mentionedaliphatic (mono-, di-, tri-) carboxylic acids (acetic acid, propionicacid, isobutyric acid, caproic acid, caprylic acid, lactic acid, maleicacid, pyruvic acid, oxalic acid, succinic acid, tartaric acid, etc.),aromatic carboxylic acids (phthalic acid, salicylic acid, benzoic acid,acetylsalicylic acid, etc.), alkylsulfonic acids (methanesulfonic acid,ethanesulfonic acid, propylsulfonic acid, butanesulfonic acid,polyoxyethylenealkylether sulfonic acid, etc.), alkylsulfonic acidderivatives (N-2-hydroxyethylpiperidine-N′-2-ethanesulfonic acid, etc.)and cholic acid derivatives (dehydrocholic acid, etc.), among whichmonocarboxylic acids or alkylsulfonic acids are preferred, and aceticacid is particularly preferred. These organic acids may be used as theirsalts, or as mixtures of the organic acids with their salts.

Such organic acids and/or their salts are suitably added in the range ofpreferably 0.01-20 wt %, more preferably 0.1-15 wt % and even morepreferably 0.1-10 wt % based on the weight of the total composition ofthe pressure-sensitive adhesive layer, taking into account skinpermeation of the drug and irritation of the skin. With a content ofless than 0.01 wt %, the skin permeation of the drug will tend to beless than sufficient, and with a content of more than 20 wt %, skinirritation will tend to occur more readily.

The pressure-sensitive adhesive layer in the patch of the invention mayalso contain a absorption enhancer. The absorption enhancer may be anycompound previously known to have absorption enhancing action into theskin, and as examples there may be mentioned:

(1) C6-20 fatty acids, aliphatic alcohols, fatty acid esters, fatty acidamides and fatty acid ethers (any of which may be saturated orunsaturated, or cyclic, straight-chain or branched),

(2) aromatic organic acids, aromatic alcohols and aromatic organic acidesters or ethers, and

(3) lactates, acetates, monoterpene-based compounds, sesquiterpene-basedcompounds, Azone, Azone derivatives, glycerin fatty acid esters,propyleneglycol fatty acid esters, sorbitan fatty acid esters(Span-type), polysorbates (Tween-type), polyethyleneglycol fatty acidesters, polyoxyethylene hydrogenated castor oils (HCO-based),polyoxyethylene alkyl ethers, sucrose fatty acid esters, vegetable oils,and the like.

Specifically, there are preferred caprylic acid, capric acid, caproicacid, lauric acid, myristic acid, palmitic acid, stearic acid,isostearic acid, oleic acid, linolic acid, linolenic acid, laurylalcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetylalcohol, methyl laurate, hexyl laurate, diethanolamide laurate,isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetylpalmitate, salicylic acid, methyl salicylate, ethylene glycolsalicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate,lauryl lactate, ethyl acetate, propyl acetate, geraniol, thymol,eugenol, terpineol, 1-menthol, borneolol, d-limonene, isoeugenol,isoborneol, nerol, dl-camphor, glycerin monocaprylate, glycerinmonocaprate, glycerin monolaurate, glycerin monooleate, sorbitanmonolaurate, sucrose monolaurate, polysorbate 20, propylene glycol,propylene glycol monolaurate, polyethylene glycol monolaurate,polyethylene glycol monostearate, polyoxyethylene lauryl ether, HCO-60,pyrothiodecane and olive oil, among which there are particularlypreferred lauryl alcohol, myristyl alcohol, isostearyl alcohol,diethanolamide laurate, glycerin monocaprylate, glycerin monocaprate,glycerin monooleate, sorbitan monolaurate, propylene glycol monolaurate,polyoxyethylene lauryl ether and pyrothiodecane.

Such absorption enhancers may also be used in combinations of two ormore, and are suitably added in the range of preferably 0.01-20 wt %,more preferably 0.05-10 wt % and even more preferably 0.1-5 wt %, basedon the weight of the total composition of the pressure-sensitiveadhesive layer, taking into account adequate permeability as a patch,and reducing irritation of the skin which may include redness, edema orthe like.

A plasticizer may also be added to the pressure-sensitive adhesive layerin the patch of the invention. As such plasticizers there may bementioned petroleum-based oils (paraffin-based processed oils,naphthene-based processed oils, aromatic-based processed oils, etc.),squalane, squalene, vegetable oils (olive oil, camellia oil, castor oil,tall oil, peanut oil, etc.), silicone oil, dibasic acid esters (dibutylphthalate, dioctyl phthalate, etc.), liquid rubbers (polybutene, liquidisoprene rubber, etc.), liquid fatty esters (isopropyl myristate, hexyllaurate, diethyl sebacate, diisopropyl sebacate, etc.), diethyleneglycol, polyethylene glycol, glycol salicylate, propylene glycol,dipropylene glycol, triacetin, triethyl citrate and crotamiton.Particularly preferred among these are liquid paraffin, liquidpolybutene, crotamiton, isopropyl myristate, diethyl sebacate and hexyllaurate.

Such plasticizers may also be used in combinations of two or more, andthe content of such plasticizers based on the total composition of thepressure-sensitive adhesive layer is preferably 5-70 wt %, morepreferably 10-60 wt % and even more preferably 10-50 wt %, taking intoaccount adequate permeability and maintaining sufficient cohesive forceas a patch.

A tackifier may further be added to the pressure-sensitive adhesivelayer in the patch of the invention. As such tackifiers there may bementioned rosin derivatives (rosins, rosin glycerin esters, hydrogenatedrosins, hydrogenated rosin glycerin esters, rosin pentaerythritolesters, etc.), alicyclic saturated hydrocarbon resins (ALCON P100(Arakawa Chemical Co., Ltd.), etc.), aliphatic hydrocarbon resins(QUINTON B-170 (Nihon Zeon), etc.) terpene resins (KURIALON P-125(Yasuhara Chemical), etc.), maleic acid resins, and the like.Particularly preferred among these are hydrogenated rosin glycerinesters, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbonresins and terpene resins.

The tackifier content based on the total composition of thepressure-sensitive adhesive layer is in the range of preferably 5-70 wt%, more preferably 5-60 wt % and even more preferably 10-50 wt %, takinginto account adequate adhesive force as a patch and reducing irritationof the skin during peeling.

If necessary, the pressure-sensitive adhesive layer in the patch of theinvention may also contain other added antioxidants, fillers,crosslinking agents, preservatives, ultraviolet absorbers and the like.As antioxidants there are preferred tocopherols and their esterderivatives, ascorbic acid, ascorbic stearic acid esters,nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT) andbutylhydroxyanisole. As fillers there are preferred calcium carbonate,magnesium carbonate, silicates (for example, aluminum silicate andmagnesium silicate), silicic acid, barium sulfate, calcium sulfate,calcium zincate, zinc oxide and titanium oxide. As crosslinking agentsthere are preferred thermosetting resins such as amino resins, phenolresins, epoxy resins, alkyd resins and unsaturated polyesters,isocyanate compounds and block isocyanate compounds, organiccrosslinking agents, and inorganic crosslinking agents such as metalsand metal compounds. As preservatives there are preferred ethylparaoxybenzoate, propyl paraoxybenzoate and butyl paraoxybenzoate. Asultraviolet absorbers there are preferred p-aminobenzoic acidderivatives, anthranilic acid derivatives, salicylic acid derivatives,coumarin derivatives, amino acid-based compounds, imidazolinederivatives, pyrimidine derivatives and dioxane derivatives.

Such antioxidants, fillers, crosslinking agents, preservatives andultraviolet absorbers are suitably added in the range of preferably notmore than 10 wt %, more preferably not more than 5 wt % and even morepreferably not more than 2 wt % based on the weight of the totalcomposition of the pressure-sensitive adhesive layer of the patch.

The pressure-sensitive adhesive layer having the composition describedabove may be fabricated by any of the following methods. Specifically,the drug-containing base component may be heated to melting and coatedonto the release sheet or backing layer, and then attached onto thebacking layer or release sheet. Alternatively, the drug-containing basecomponent may be dissolved in a solvent such as toluene, hexane or ethylacetate, spread onto the release sheet or backing layer and dried forremoval of the solvent, and then attached to the backing layer orrelease sheet to give a patch.

The patch of the invention is sufficient if it is a patch comprising adrug-containing pressure-sensitive adhesive layer laminated on thepolyester film side of a laminated backing layer consisting of theaforementioned knitted fabric laminated on the polyester film, and thereare no additional restrictions on the composition, construction orvarious component materials, or on their types.

The pressure-sensitive adhesive layer may also be provided with arelease sheet layer, and for example, there may be used release sheetsselected from films of silicon-treated polyesters (polyethyleneterephthalate, etc.), polyvinyl chloride and polyvinylidene chloride,laminated films of woodfree paper and polyolefins, and the like,laminated on the contact side of the pressure-sensitive adhesive layer.

EXAMPLES

The present invention will now be explained in greater detail based onexamples and comparative examples, with the understanding that theinvention is not limited to the examples, and various modifications maybe incorporated which are not outside of the technical scope of theinvention. Throughout the examples and comparative examples, the entire“%” refers to “wt %”, unless otherwise specified.

Example 1

(Fabrication of a Backing Layer)

A polyethylene terephthalate knitted fabric with a 30% longitudinalmodulus of 8.5 kg/5 cm, a 30% lateral modulus of 2.7 kg/5 cm (30%longitudinal modulus/30% lateral modulus ratio of 3.14) and a basisweight of 120 g/m² was bonded to a polyethylene terephthalate film witha thickness of 6 μm, a longitudinal ductility of 12.5% and a lateralductility of 20.6% using an adhesive comprising styrene-isoprene-styreneblock copolymer (CALIFLEX TR1107, product of Shell Chemical) and aterpene-based resin (YS resin PX-1150, Yasuhara Chemical) to fabricate alaminated backing layer. The thickness of the obtained laminated backinglayer was 0.55 mm, and the stiffness was 18.5 mg.

(Fabrication of a Patch)

Procaterol hydrochloride, lauryl alcohol, sodium acetate and liquidparaffin were measured into a mortar and thoroughly mixed, and theobtained mixture was added to a mixed solution consisting ofstyrene-isoprene-styrene block copolymer, an acrylic-based polymer(DURO-TAK87-4098, National Starch & Chemicals), an alicyclic saturatedhydrocarbon resin (ALCON P100, Arakawa Chemical Co., Ltd.), ethylacetate and toluene, to prepare a coating solution having the followingcomposition (without solvent): Styrene-isoprene-styrene block copolymer18.0% Acrylic-based polymer 22.0% Alicyclic saturated hydrocarbon resin29.5% Liquid paraffin 19.5% Lauryl alcohol  3.0% Sodium acetate  3.0%Procaterol hydrochloride  5.0%

The obtained coating solution was then coated onto a polyethyleneterephthalate release film and the solvent was removed by drying to forma pressure-sensitive adhesive layer (thickness: 75 μm). Thepressure-sensitive adhesive layer was spread onto the exposed side ofthe polyethylene terephthalate film of the previously fabricatedlaminated backing layer to give a patch.

Comparative Example 1

A patch was obtained in the same manner as Example 1, except that thepressure-sensitive adhesive layer was spread onto the exposed side ofthe polyethylene terephthalate knitted fabric of the laminated backinglayer.

Comparative Example 2

A patch was obtained in the same manner as Example 1, except that apolyethylene film (thickness: 50 μm) was used instead of thepolyethylene terephthalate film.

Comparative Example 3

A patch was obtained in the same manner as Example 1, except that abacking layer composed only of a polyethylene terephthalate knittedfabric was used instead of the laminated backing layer.

Example 2

Fentanyl citrate, pyrothiodecane, sodium acetate and liquid paraffinwere measured into a mortar and thoroughly mixed, and the obtainedmixture was added to a mixed solution consisting ofstyrene-isoprene-styrene block copolymer, polyisobutylene, an alicyclicsaturated hydrocarbon resin (ALCON P100, product of Arakawa ChemicalCo., Ltd.) and toluene, to prepare a coating solution having thefollowing composition (without solvent): Styrene-isoprene-styrene blockcopolymer 16.5% Polyisobutylene 11.0% Alicyclic saturated hydrocarbonresin 34.5% Liquid paraffin 29.5% Pyrothiodecane  3.0% Sodium acetate 1.5% Fentanyl citrate  4.0%

A patch was obtained in the same manner as Example 1, except for the useof this coating solution.

Comparative Example 4

A patch was obtained in the same manner as Example 2, except that thepressure-sensitive adhesive layer was spread onto the exposed side ofthe polyethylene terephthalate knitted fabric of the laminated backinglayer.

Comparative Example 5

A patch was obtained in the same manner as Example 2, except that a softvinyl chloride film (thickness: 100 μm) was used instead of thepolyethylene terephthalate film.

Comparative Example 6

A patch was obtained in the same manner as Example 2, except that abacking layer composed only of a polyethylene terephthalate knittedfabric was used instead of the laminated backing layer.

Hairless Mouse Drug Skin Permeation Test

Dorsal skin of hairless mice was peeled off and fixed in a flow-throughcell (5 cm²) having peripherally circulating 37° C. warm water, with thedermal side as the receptor layer side. The patches obtained in Examples1 and 2 and Comparative Examples 1-6 were attached to the horny layerside and, using physiological saline as the receptor layer, sampling wascarried out at speed of 5 ml/hr every 2 hours for a period of 24 hours.For the receptor solutions obtained at each interval, the flow rate wasprecisely measured, the drug concentration was measured byhigh-performance liquid chromatography, the drug permeation rate perhour was calculated and the drug skin permeation rate per unit area in astationary state was determined. Samples with large permeation rateswere judged as having excellent percutaneous absorbency. The results areshown in Table 1. TABLE 1 Drug skin permeation rate (μg/m²/hr) Example 13.4 Comparative Example 1 1.1 Comparative Example 2 1.6 ComparativeExample 3 1.0 Example 2 24.1 Comparative Example 4 11.2 ComparativeExample 5 7.5 Comparative Example 6 10.8

As clearly seen by the results in Table 1, the patches obtained inExamples 1 and 2 according to the present invention were confirmed tohave notably improved drug skin permeation rates compared to the patchesobtained in Comparative Examples 1-6 which were outside the scope of theinvention, given the same pressure-sensitive adhesive layer composition.

Examples 3-10 and Comparative Examples 7-12

(Fabrication of Baking Layers)

Polyethylene terephthalate knitted fabrics having the 30% longitudinalmoduli, 30% lateral moduli and basis weights shown in Tables 2 and 3were bonded to polyethylene terephthalate films having the longitudinalductilities, lateral ductilities and thicknesses shown in Tables 2 and 3using an adhesive comprising styrene-isoprene-styrene block copolymer(CALIFLEX TR1107, Shell Chemical) and a terpene-based resin (YS resinPX-1150, Yasuhara Chemical) to fabricate laminated backing layers. Thethicknesses and stiffnesses of the obtained laminated backing layers areshown in Tables 2 and 3.

(Fabrication of Patches)

Ketoprofen, 1-menthol and liquid paraffin were measured into a mortarand thoroughly mixed, and the obtained mixture was added to a mixedsolution comprising styrene-isoprene-styrene block copolymer,polyisobutylene, a hydrogenated rosin ester (KE-311, product of ArakawaChemical Co., Ltd.) and toluene, to prepare a coating solution havingthe following composition (without solvent): Styrene-isoprene-styreneblock copolymer  6.5% Polyisobutylene 24.5% Hydrogenated rosin ester36.8% Liquid paraffin 31.5% l-Menthol  0.5% Ketoprofen  0.2%

The obtained coating solution was then coated onto a polyethyleneterephthalate release film and the solvent was removed by drying to forma pressure-sensitive adhesive layer (thickness: 120 μm). Thepressure-sensitive adhesive layer was spread onto the exposed side ofthe polyethylene terephthalate film of the previously fabricatedlaminated backing layer to obtain a patch.

Example 11

A patch was obtained in the same manner as Example 3, except that aurethane-based adhesive (DIABOND DA3042M, Nogawa Chemical Co., Ltd.) wasused instead of the adhesive comprising the styrene-isoprene-styreneblock copolymer and terpene-based resin.

Comparative Example 3

A patch was obtained in the same manner as Example 3, except thatlaminated backing layers composed only of polyethylene terephthalatefilms having the longitudinal ductilities, lateral ductilities andthicknesses shown in Tables 2 and 3 were used instead of the laminatedbacking layer described above.

Organoleptic Tests

The patches fabricated in Examples 3-11 and Comparative Examples 7-13were each cut to a 20 cm² area and used for the organoleptic testsdescribed below after attachment for 8 hours onto the arms of tenvolunteers. The results of the organoleptic tests are shown in Tables 2and 3.

(Curling)

The patch was peeled from the release film and the degree of curling wasevaluated based on the following scale.

-   -   1: High degree of curling    -   2: Moderate curling    -   3: No curling

(Attachment Ease)

The patch was attached onto the skin and the attachment ease wasevaluated based on the following scale.

-   -   1: Difficult to attach    -   2: Somewhat difficult to attach but acceptable    -   3: Easy to attach

(Comfortability)

The patch was attached to the skin and the comfortability was evaluatedbased on the following scale.

-   -   1: Lacking flexibility, uncomfortable    -   2: Somewhat lacking flexibility and slightly uncomfortable, but        acceptable    -   3: Excellent flexibility, no discomfort

(Adhesive strength)

The patch was attached to the skin and the adhesion was evaluated basedon the following scale.

-   -   1: Falling off    -   2: Unacceptable folding    -   3: Partial folding, but acceptable    -   4: Absolutely no peeling

(Cohesion Between Fabric and Film)

The degree of cohesion between the knitted fabric and film of the patchwas evaluated based on the following scale.

-   -   1: Peeling between fabric and film    -   2: Satisfactory cohesion between fabric and film, with no        interlayer peeling

(Overall Evaluation)

An overall evaluation was assigned from each of the organoleptic testevaluations, based on the following scale.

-   -   A: Very good    -   B: Good    -   C: Somewhat poor

D: Poor TABLE 2 Example 3 4 5 6 7 8 9 10 11 Knitted 30% Longitudinal 7.113.6 16.9 4.7 0.9 0.9 0.9 0.9 7.1 fabric modulus (kg/5 cm) 30% Lateralmodulus 1.6 5.2 6.8 0.9 0.4 0.4 0.4 0.4 1.6 (kg/5 cm) 30% Longitudinal4.44 2.62 2.49 5.22 2.25 2.25 2.25 2.25 4.44 modulus/30% Lateral modulusBasis weight (g/m²) 89 178 35 122 95 95 95 95 90 PolyethyleneLongitudinal 12.5 22.1 28.1 7.2 16.7 0.05 33.6 3.3 12.5 terephthalateductility (%) film Lateral ductility 20.6 13.4 45.3 9.9 14.2 4.2 49.31.6 20.6 (%) Thickness (μm) 5 5 10 2 6 1.5 12 2 5 Stiffness (mg) 14.022.1 19.0 12.3 13.1 3.9 29.0 7.7 14.7 Backing layer 0.32 0.81 0.18 0.570.36 0.35 0.37 0.35 0.32 thickness (mm) Curling 3 3 3 3 3 3 2 3 3Attachment ease 3 3 3 3 3 3 3 3 3 Comfortability 3 2 2 3 3 2 3 2 3Adhesion 4 4 4 4 4 3 4 3 4 Fabric/film cohesion 2 2 2 2 2 2 2 2 1Overall evaluation A B B A A B B B B

TABLE 3 Comparative Example 7 8 9 10 11 12 13 Knitted 30% Longitudinalmodulus 0.03 27.2 17.4 6.2 3.4 18.3 fabric (kg/5 cm) 30% Lateral modulus0.02 9.2 12.5 7.6 0.9 7.5 (kg/5 cm) 30% Longitudinal modulus/30% 1.502.96 1.39 0.82 3.78 2.44 Lateral modulus Basis weight (g/m²) 77 106 10182 6 241 Polyethylene Longitudinal ductility (%) 12.5 12.5 38.5 22.116.7 0.05 16.7 terephthalate film Lateral ductility (%) 20.6 20.6 40.213.4 14.2 4.2 14.2 Thickness (μm) 5 5 5 5 6 1.5 6 Stiffness (mg) 9.234.2 28.6 16.4 9.7 28.8 8.3 Backing layer thickness (mm) 0.29 0.38 0.380.30 0.03 1.29 0.006 Curling 1 3 1 1 3 3 3 Attachment ease 1 3 3 1 1 3 1Comfortability 3 1 1 2 2 1 1 Adhesion 2 1 1 2 3 2 2 Fabric/film cohesion2 2 2 2 2 2 — Overall evaluation D D D D C C D

As clearly seen by the results of organoleptic tests in Tables 2 and 3,the patches obtained in Examples 3-11 according to the present inventionwere confirmed to maintain at satisfactory levels with a good balance,the occurrence of curling, the ease of attachment, the comfortability,the adhesion strength and the cohesion between fabrics and filmscompared to the patches obtained in Comparative Examples 7-13 which wereoutside the scope of the invention.

Industrial Applicability

According to the present invention, as explained above, it is possibleto obtain a patch which has excellent flexibility, exhibits no curlingand uses a backing layer which does not adsorb the drug. Consequently,it is easy to attach and has excellent adhesion and comfortability,while the lack of adsorption of the drug into the backing layer alsoensures adequate skin permeation of the drug.

1. A patch comprising a laminated backing layer and a drug-containingpressure-sensitive adhesive layer, wherein the laminated backing layerconsists of a knitted fabric laminated on one side of a polyester film,and the drug-containing pressure-sensitive adhesive layer is laminatedon the other side of the polyester film, wherein the knitted fabric hasa 30% longitudinal modulus of 0.1 kg/5 cm to 20 kg/5 cm and a 30%lateral modulus of not more than 10 kg/5 cm, and a 30% longitudinalmodulus/30% lateral modulus ratio of not less than
 2. 2. A patchaccording to claim 1, wherein the polyester film has a longitudinalductility of not less than 0.5% and less than 30%.
 3. A patch accordingto claim 1, wherein the polyester film has a lateral ductility of notless than 2% and a thickness of 0.5-12 μm.
 4. A patch according to claim1, wherein the stiffness of the laminated backing layer is not more than30 mg.
 5. A patch according to claim 1, wherein the basis weight of theknitted fabric is 10 g/m² to 200 g/m² and the thickness of the laminatedbacking layer is 0.05-1 mm.
 6. A patch according to claim 1, wherein theknitted fabric is a polyester knitted fabric.
 7. A patch according toclaim 1, wherein the knitted fabric and the polyester film are gluedtogether by an adhesive comprising a hydrocarbon-based polymer and atackifier.
 8. A patch according to claim 7, wherein saidhydrocarbon-based polymer is styrene-isoprene-styrene block copolymer.